Pharmaceutical agents containing diphosphonic acids and salts thereof

ABSTRACT

PCT No. PCT/EP93/02217 Sec. 371 Date Feb. 24, 1995 Sec. 102(e) Date Feb. 24, 1995 PCT Filed Aug. 19, 1993 PCT Pub. No. WO94/05297 PCT Pub. Date Mar. 17, 1994The invention concerns pharmaceutical preparations that are stable on storage, which contain at least one diphosphonic acid and/or at least one physiologically acceptable salt of such an acid as the active substance.

This application is a 371 of PCT/EP93/02217.

The invention concerns well-tolerated injection solutions that arestable when stored in primary packaging made of glass and contain atleast one diphosphonic acid or at least one physiologically acceptablesalt of such an acid, processes for producing these solutions and theuse of polyethylene glycols to stabilize these solutions.

Diphosphonic acids within the sense of the present invention arecompounds which have already been introduced some time ago intotherapeutic practice for the treatment of disorders of calciummetabolism.

These compounds are of particular interest for the treatment ofhypercalcaemia and are used as active substances in therapeutic agentsfor the treatment of osteoporosis and in tumour osteolysis. The efficacyof disphosphonates (sodium etidronate, dichloromethylene-diphosphonate,aminohydroxypropane-, aminohydroxybutane-aminohydroxypentane-,aminohydroxyhexane-diphosphonate, and others) in inhibitingbone-reabsorption which is increased in an unnatural manner in many bonediseases such as e.g. Morbus Paget, in bone tumours, in bone metastases,in osteoporosis or in hyperparathyroidism, has already been known for along time.

Diphosphonates as pharmaceutical agents are described for example in EP0 170 228; EP 0 197 478; EP 0 224 751; EP 0 252 504; EP 0 252 505; EP 0258 618; EP 0 350 002; EP 0 273 190; WO 90/00798.

Solid forms of administration for pharmaceutical agents containingdiphosphonates in the form of preparations containing effervescents aredescribed in DE 3 500 670.

Diphosphonic acids and salts thereof are in principle readily soluble inwater and are usually quite stable substances with regard to temperatureinfluences. In the production of injection solutions which had beenadjusted to the pH value of blood (pH value 7.4), the solutionsunexpectedly became turbid on longer storage despite the good solubilityof the active substances. In addition it turned out that the content ofactive substance in the injection solutions in the glass vessels becamecontinuously lower on storage over a long period of time even when thesolutions did not yet exhibit any turbidity. The reasons for thisreduction is the content of active substance are unclear.

Injection solutions are usually filled into primary packaging made ofglass (e.g. ampoules, vials, ready-to-use syringes, carpoules) in whichcase the glass ampoules used for pharmaceutical purposes are usuallycomposed of glasses of hydrolytic class I. The chemical stability ofglass vessels for pharmaceutical use is assessed by determining soluble,mineral substances that are released into water under standardizedconditions. In this process the contact of the water with the innersurface of the vessel or with powdered glass is stipulated. Thehydrolytic resistance is determined by titrating the hydroxide ions thatare formed in the solution. The glass vessels are classified into fourtypes of glass according to their hydrolytic resistance. Glass of classI is composed of neutral glass with a high hydrolytic resistance due tothe chemical composition of the glass as such. Glass of class II isusually composed of soda-lime-silicate glass and has a high hydrolyticresistance due to appropriate surface treatment. Glass of class III isusually composed of soda-lime-silicate glass and has a medium hydrolyticresistance. Glass of class IV is composed of soda-lime-silicate glassand has a low hydrolytic resistance.

Despite the use of glass containers of hydrolytic class I it wasestablished that the content of aluminium ions in the injectionsolutions continuously increased on longer storage.

Due to these three disadvantageous findings on longer storage of thesolutions--turbidities, reduction in the content of active substance andincrease of the aluminium content--such solutions must be labelled asbeing physically unstable with regard to the intended official licenceand registration as pharmaceutical agents. In addition it is alsoundesirable from a medical point of view to administer solutions whenthey have an increased aluminium content.

The object of the invention was therefore to provide injection solutionsof diphosphonic acids or of their salts which are stable up to 5 yearswhen stored in glass containers and which are well-tolerated whenadministered to humans.

It has now been found that injection solutions containing at least onediphosphonic acid or at least one acceptable salt or ester of such anacid that are stable in glass containers can be prepared when thesesolutions have a pH value between about 3.0 and 4.5 and/or containpolyethylene glycols and optionally are filled into glass containersthat are surface treated.

Surprisingly aluminium concentrations are achieved that are less than 2ppm, the content of active substances in the solution remains constantand no turbidities occur. The pH value of the solutions is preferably atabout 4. The solutions are stable for up to 5 years on storage at roomtemperature. Moreover it was found that the solution of pharmaceuticalagent is well-tolerated when administered intravenously despite the lowpH value and is thus well-suited for administration to humans.

The addition of polyethylene glycols to the solution has the same effectas lowering the pH value. The polyethylene glycols that can be usedusually have a molar weight between 100 and 1500, in particular of200-600. Macrogol® is preferably used. FIG. 1 illustrates the reductionof the aluminium content of the solution when Macrogol® is added. Theamount of added polyethylene glycols can be up to 20 volume percent.5-10% of the polyethylene glycols is preferably used. In particular 1 mlinjection solution contains 0.05 to about 0.2 ml Macrogol®.

An even stronger reduction of the aluminium content is achieved bycombining both measures--reducing the pH value to about 3.0-4.5 andaddition of polyethylene glycol (cf. FIG. 2).

The concentration of aluminium ions can be reduced further by fillingthe injection solution into the glass ampoules, if desired, under aninert gas atmosphere. For example gassing the solution with nitrogenduring its production leads to comparable results. As a further measureto reduce the aluminium content, the surface of the glass container canbe optionally treated. In the treatment a thin surface layer is producedon the inside of the ampoule glass by for example evaporation coatingwith ammonium sulfate, sulphur dioxide, sulphur trioxide or ammoniumchloride.

The invention is described in the following on the basis of examplessome of which are illustrated by diagrams.1-Hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid (=A),dichloromethane-diphosphonic acid (=B, clodronate) and3-amino-1-hydroxypropylidene-diphosphonic acid (=C, pamidronate) areused as active substances representing the group of diphosphonates in asuitable solution for injection. The active substance A is described inthe European Application EP 0 252 505. In principle it is also possibleto use other diphosphonic acids or physiologically acceptable saltsthereof or physiologically acceptable esters thereof in a correspondingmanner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 show diagrammatically the relationship between thealuminium content of the injection solutions described in examples 9 to15 and the factors pH value, addition of auxiliary substance and storagetime.

EXAMPLES 1 TO 9

The injection solutions described in examples 1 to 9 contained in eachcase 1.069 mg sodium salt of1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid and 8.6mg NaCl per ml aqueous solution. The components or properties which werenot identical in all solutions are listed in Table 1. The pH values wereadjusted by adding appropriate amounts of NaOH or HCl. The solutionswere filled into ampoules made of glass of hydrolytic class I. Thesolutions were sterilized for 20 minutes at 121° C. before storage.Before and after the sterilization and after a storage period of sixweeks at 50° C., the aluminium content in the solutions was determinedby means of AAS (atomic absorption spectroscopy). The aluminiumvalues--averaged over 10 solution samples per example in each case--arealso listed in Table 1.

                  TABLE 1                                                         ______________________________________                                                             Macrogol                                                                             Al content [ppm]                                                                          after                                 Ex.         N.sub.2  [mg/ml before after  6                                   No.  pH     gassing  sol.]  steril.                                                                              steril.                                                                              weeks                               ______________________________________                                        1    3                      0.4    0.9    1.0                                 2    4                      0.2    0.4    1.1                                 3    4.5                    0.2    0.5    1.2                                 4    5                      0.3    0.6    1.8                                 5    6                      0.6    1.3    4.5                                 6    6      +               0.4    0.8    4.6                                 7    6               0.2    0.3    0.4    1.2                                 8    6                      0.3    0.7    4.4.sup.1)                          9    7                      1.2    2.1    4.3                                 ______________________________________                                         .sup.1) Addition of propylene glycol (0.2 ml per 1 ml solution)          

The results show that low pH values and/or the addition of apolyethylene glycol such as e.g. Macrogol (see example 7) are able tokeep the aluminium content particularly low and that N₂ gassing duringthe production of the solution at least initially contributes to alowered aluminium content of the solutions and that although theaddition of other solvents with organic hydroxyl groups also reduces thealuminium content of the solution (see example 8), this is, however,much less than in the case of polyethylene glycols.

EXAMPLE 10 TO 16

The injection solutions described in examples 10 to 16 contained in eachcase 1.12 mg sodium salt of1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid and 8.6mg NaCl per ml aqueous solution. The solutions were gassed with nitrogenduring their production. The components or properties which were notidentical in all solutions are listed in Table 2. The pH value inexample 16 was adjusted by adding an appropriate amount of NaOH. Thesolutions of examples 10 to 13 were filled into ampoules made of glassof hydrolytic class I and those of solutions 14 to 16 were filled intoOPC ampoules the surface of which had been treated with ammoniumsulfate. The solutions were sterilized for 20 minutes at 121° C. beforestorage. After sterilization and after storage periods of 6 and 13 weeksat 50° C., the aluminium content in the solutions was determined bymeans of AAS. The aluminium values--averaged over 10 solution samplesper example in each case--are also listed in Table 2.

                  TABLE 2                                                         ______________________________________                                                      Macrogol      Al content [ppm]                                                                          after                                 Ex.  treated  [ml/ml        before after  13                                  No.  glass    sol.]    pH   steril.                                                                              6 weeks                                                                              weeks                               ______________________________________                                        10                     4    0.5    1.4    2.4                                 11            0.05     4    0.6    1.2    1.6                                 12            0.10     4    0.7    1.2    1.7                                 13            0.20     4    0.6    1.0    2.1                                 14   +                 4    0.1    1.0    2.1                                 15   +        0.20     4    0.1    0.3    0.6                                 16   +                 6    0.8    4.5    5.9                                 ______________________________________                                    

The aluminium values during the storage period of the solutionsaccording to the invention described in examples 11 to 13 and 14 to 16and in comparison to the aluminium values of the solution described inexample 10 which only had N₂ gassing as the inventive feature as used inall examples of the second series to reduce the aluminium content in theinjection solutions, are plotted in FIGS. 1 and 2.

The results show--similar to those achieved in the first series ofexamples--that Macrogol considerably reduces the aluminium content (seeexamples 11-13) and smaller amounts appear to be even more effectivethan larger amounts. They also show that treated glass alone (seeexample 14) or together with Macrogol (see example 15) forms a barrieragainst the dissolution of aluminium, but also that the effect of a highpH value cannot be blocked by treated glass (see example 16).

EXAMPLE 17

Investigations on the stability of solutions in relation to the pH valueof the solutions.

The following active substances were used to prepare the injectionsolutions:

A=1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid;concentration: 1 mg/ml

B=1,1-dichloro-1,1-diphosphonic acid, Na salt×4 H₂ O; concentration: 300mg/10 ml

C=3-amino-1-hydroxypropylidene-diphosphonic acid; concentration: 3 mg/ml

The aluminium determinations were carried out by AAS. The stated dataare means of five or ten determinations. The injection solutions wereprepared according to the following protocol: The active substance isdissolved in water for injection purposes and the desired pH value isadjusted with NaOH or HCl. In the case of the active substance B, thedesired pH value is adjusted with sodium bicarbonate. The filling intoampoules is carried out under aseptic conditions after filtration oversterilized membrane filters of pore size 0.2 μm. Solutions containingactive substances A and C were additionally sterilized at 121° C. Glassampoules of hydrolytic class I were used.

                  TABLE 3                                                         ______________________________________                                                                    Storage                                           Active          Temp.       period                                                                              A1 content                                  substance pH    [0° C.]                                                                            (month)                                                                             [ppm]                                       ______________________________________                                        --        6     21-25       19    0.3                                         A         6     21-25       8     3.2                                         A         6     50          1.5   4.4                                         A         5     50          1.5   1.8                                         A         4     50          1.5   1.1                                         A         4     50          3     1.3                                         A         4     30          3     0.7                                         A         3     50          1.5   1.0                                         B         5.7   25          22    3.6                                         B         4.3   25          21    0.6                                         C         4.3   50          3     1.9                                         C         6.5   50          3     3.9                                         ______________________________________                                    

As can be seen in the above table the aluminium content of the injectionsolution increases when the solutions have a pH value which is near tothe pH value of blood and when the solutions are stored under stress.The stronger stressing of the samples can be achieved by longer storageat room temperature or by storage at increased temperatures over acorrespondingly shorter time period. Solutions which have a pH value ofunder 5 have a comparably lower aluminium content.

EXAMPLE 18

The injection solutions described in example 18 contain in each case 3mg Pamidronate=APD=3-amino-hydroxypropylidene-bisphosphonic acid per mlaqueous solution. In the production of the solutions the pH value isadjusted to 4, 5, 6 with small amounts of NaOH. In each case 1 ml of thesolutions was filled into 1 ml glass ampoules of hydrolytic class I. Theampoules were stored at room temperature (21°-25° C.) and at 50° C. andthen the aluminium content in the solutions was determined by means ofAAS. The means of 5 measurements in each case are shown in Table 4 inrelation to the storage temperature and pH. It is clear from the datathat lowering the pH value from 6 to 5 or 4 decreases the aluminiumcontents to ca. 50%.

                  TABLE 4                                                         ______________________________________                                        Aluminium ions in glass ampoules containing Pamidronate                       (APD) 3 mg/1 ml injection solution                                                                          A1 content (ppm)                                pH value of                                                                             Storage             per ampoule                                     the injection                                                                           period    Temperature                                                                             mean of 5                                       solution  (weeks)   stress    measurements                                    ______________________________________                                        4         8         RT        0.46                                            4         8         RT        0.46                                            4         8         50° C.                                                                           0.72                                            4         8         50° C.                                                                           0.84                                            5         8         RT        0.54                                            5         8         RT        0.47                                            5         8         50° C.                                                                           1.00                                            5         8         50° C.                                                                           0.65                                            6         8         RT        0.80                                            6         8         RT        0.75                                            6         8         50° C.                                                                           1.68                                            6         8         50° C.                                                                           1.40                                            ______________________________________                                         RT = room temperature                                                    

EXAMPLE 19

The injection solutions described in example 19 contain in each case1.069 mg sodium salt of1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid and 8.6mg NaCl per ml aqueous solution. The pH value was adjusted with 0.5 mgacetic acid and 0.2 mg sodium acetate (3 H₂ O). The solutions werefilled into glass ampoules of hydrolytic class I and sterilized for 20minutes at 121° C. before storage.

After an appropriate storage period the aluminium content in thesolution was determined by means of AAS. The results are shown in Table5. All solutions were clear after storage and had the complete amount ofactive substance. The tolerance of these preparations after i.v.injection was very good.

    ______________________________________                                                                           A1 content                                                             pH value                                                                             (ppm) per                                  Injection                                                                             Storage Temperature of the ampoule                                    solution                                                                              period  stress      injection                                                                            mean of 5                                  No.     (weeks) °C.  solution                                                                             measurements                               ______________________________________                                        19.1    52      6-8         3.9    0.47                                       19.1    52      25          3.9    0.6                                        19.1    52      30          4.0    0.73                                       19.2    52      6-8         4.3    0.58                                       19.2    52      25          4.3    1.0                                        19.2    52      30          4.3    1.18                                       19.3    52      6-8         4.1    0.13                                       19.3    52      25          4.1    0.16                                       19.3    52      30          4.1    0.28                                       19.4    52      6-8         4.3    0.39                                       19.4    52      25          4.3    0.63                                       19.4    52      30          4.3    0.77                                       ______________________________________                                    

We claim:
 1. Injection solution which is stable on storage in a glasscontainer, said solution being an aqueous solution containing at leastone bone-reabsorption-inhibiting diphosphonic acid or physiologicallyacceptable salt or ester thereof as the active substance, said solutionbeing stabilized by having a pH value of the solution of about 3.0 to4.5 or by having a pH value of the solution of about 3.0 to 4.2 and thepresence of polyethylene glycols.
 2. Solution of claim 1, wherein the pHvalue of the solution is of about 3.0 to 4.5 and the solution containspolyethylene glycols.
 3. Solution of claim 1, wherein the pH value ofthe solution is about
 4. 4. Solution of claim 1, wherein the solutioncontains up to 20% of polyethylene glycols having a molecular weight ofabout 200-1500.
 5. Solution of claim 4, wherein the solution containsabout 0.05 to about 0.2 ml of polyethylene glycols per 1 ml of injectionsolution.
 6. Solution of claim 1, wherein the solution contains at leastone 1-hydroxy-aminoalkyl-1,1-diphosphonic acid or physiologicallyacceptable salt or ester thereof as the active substance.
 7. Solution ofclaim 6, wherein the active substance is 1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid or physiologically acceptable saltthereof.
 8. Solution of claim 1, wherein the active substance is in theform of a pharmaceutically acceptable alkali salt.
 9. Solution of claim1, wherein the solution contains the active substance in an amount ofabout 0.1 to about 1000 mg and NaCl in an amount of less than 10 mg/mlof aqueous solution.
 10. A kit comprising a glass container containingan aqueous injection solution of at least one physiologically acceptablebone-reabsorption-inhibiting diphosphonic acid or salt or ester thereofas the active ingredient, said solution being stable on storage in thecontainer for up to 5 years, said solution having a pH value of about3.0-4.5.
 11. A kit comprising a glass container containing onephysiologically acceptable bone-reabsorption-inhibiting diphosphonicacid or salt or ester thereof as the active ingredient, said solutionbeing stable on storage in the container for up to 5 years, saidsolution containing polyethylene glycols and having a pH value of about3.0-4.5.
 12. A method for stabilizing an aqueous injection solution forthe treatment of bone diseases, said solution being storage stable forup to 5 years and containing as the active substance at lease onebone-reabsorption-inhibiting diphosphonic acid or physiologicallyacceptable salt or ester thereof, said solution being stored in a glasscontainer, said method comprising adjusting the pH Value of the solutionto about 3.0-4.5 prior to filling the glass container with the solution.13. A method for stabilizing an aqueous injection solution for thetreatment of bone diseases, said solution being storage stable for up to5 years and containing as the active substance at lease onebone-reabsorption-inhibiting diphosphonic acid or physiologicallyacceptable salt or ester thereof, said solution being stored in a glasscontainer, said method comprising adjusting the pH to about 3.0 to 4.5and adding polyethylene glycols to the solution.
 14. Method of claim 12,wherein the glass container has been surface-treated before being filledby the solution.
 15. Method of claim 12, wherein the pH value isadjusted to about 4.0.
 16. Method of claim 13, wherein the glasscontainer has been surface-treated before being filled by the solution.17. Method of claim 13, wherein the pH value is adjusted to about 4.0.18. Solution of claim 1, wherein the solution is stabilized by having apH value of 3 to 4.5, and the solution is free of polyethylene glycols.19. The kit of claim 10 wherein the glass container has been surfacetreated.
 20. The kit of claim 19 wherein the glass container has beensurface treated with ammonium sulfate, sulfur dioxide, sulfur trioxideor ammonium chloride.
 21. The kit of claim 11 wherein the glasscontainer has been surface treated.
 22. The kit of claim 21 wherein theglass container has been surface treated with ammonium sulfate, sulfurdioxide, sulfur trioxide or ammonium chloride.